Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008

nucleus, where they terminate in the nuclear region that has connections to the oculorotatory nuclei via the MLF.

Age-related changes in the neural input to the cerebellum, as described above, would interfere with a variety of visual reflexes, as well as voluntary based eye movements. The role of the vestibular system, proprioception, and cortical input is therefore worthy of some further consideration and will be dealt with.

Age-related Changes in the Vestibulocerebellar Pathway

The cerebellum influences posture, balance, and equilibrium through the vestibulocerebellar pathways to axial and proximal limb muscles. Vestibulocerebellar dysfunction, caused by age-related changes or pathological conditions, are hence likely to result in unsteady gait and ataxic movements. The vestibular nuclei also innervate the three oculorotatory cranial nerves, and the role of the cerebellum has therefore been studied in modifiability of the vestibule-ocular reflex (VOR). When the head is turned to the left, there is a reflex tendency for the eyes to turn to the right. A three-neuron arc connects the horizontal semicircular canals to the extraocular motor neurons so that rotation of the head tends to produce an equal and opposite movement of the eyes—thus stabilizing the gaze. If the vestibule-ocular reflex fails to compensate completely for head movements, the image on the retina slips when the head is turned. It has been suggested that a mismatch of this sort between the vestibular input and the eye movement can be detected and forwarded to the flocculus located in the flocculondular lobe of the cerebellum. Purkinje cells in the flocculus can then serve to adjust the vestibule-ocular reflex.15

The sensory cells of the three semicircular canals convey their information through the short preganglionic nerve fibers of the vestibular nerve. The postganglionic fibers have two destinations—the cerebellum and the vestibular nucleus. The neural pathway that terminates directly in the flocculus of the cerebellum constitutes the primary vestibulocerebellar pathway. Those fibers that have synaptic interruptions in the vestibular nucleus constitute the secondary vestibulocerebellar pathway. The cerebellum has efferent fibers returning to the vestibular nucleus and hence can influence the efferent neurons interacting with motor neurons serving extraocular muscles as well as somatic muscles. Although the neural pathways concerned with oculomotor control are the most prominent,16 some Purkinje fibers in the vermis also send fibers to the lateral vestibular nucleus, which in turn is connected to the medulla spinalis. The latter projection—the tractus vestibule spina- lis—is concerned with balance and movement of the extremities. Simultaneous contraction of somatic muscles and extraocular muscles are hence facilitated by these neural pathways, and compensatory rotations of the eye can be executed following head or body movements (Fig. 20.5).

The vestibular system is capable of affecting both horizontal and vertical eye movements through ascending fibers in the medial longitudinal fasciculus. This long-fiber tract extends from the lower aspects of the brainstem up to the III nerve

Fig. 20.5 The figure illustrates a vestibulocerebellar pathway. The primary afferent vestibulocerebellar pathway terminates directly in the cerebellum, while the secondary vestibulocerebellar pathway has a synaptic interruption in the vestibular nucleus before it terminates in the cerebellum (blue lines). The efferent fibers returning to the vestibular nucleus can influence those efferent neurons interacting with motor neurons serving extraocular muscles as well as somatic muscles (black lines). Drawing by IB Kjellevold Haugen

nuclear complex in the mesencephalon. Some fibers extend even further and terminate in two distinct nuclei that are referred to as the interstitial nucleus of Cajal and the rostral interstitial nucleus of the medial longitudinal fasciculus (rMLF). These nuclei are both involved in vertical gaze. The majority of the ascending fibers that travel in the ipsilateral aspect of the MLF derive from the superior aspect of the vestibular nucleus, while those fibers that cross over to the contralateral side arise from the medial aspect of the vestibular nucleus. Both components of the MLF supply (to a large extent) the oculomotor nuclei bilaterally via collaterals that cross the midline. The fibers that connect the abducens nucleus with the contralateral medial rectus subnucleus travel in the medial aspect of the MLF (Fig. 20.6).

The role of the MLF becomes evident in pathological conditions, such as internuclear ophthalmoplegia, where the patient’s ability to adduct is lost. The fact that most of these patients are still able to converge, which is an ocular movement that also requires adduction, suggests that the neural pathway for convergence does not run through the MLF.17,18 However, clinical observations of reduced ability to perform horizontal conjugate eye movements, as well as convergence insufficiency among elderly patients, suggests that both of these neural pathways may be subjected to neurogenic age-related changes.

Studies of eye movements among subjects over the age of 75 have revealed a significant reduction in speed and accuracy of the vestibule-ocular reflex (VOR) in comparison to that of younger age groups. Reduction in speed of the VOR would require a longer period of suppression of the sensory image. The ability to suppress the sensory image during the actual VOR movement is essential to maintaining orientation and focus, especially in situations where head movements and object movements occur simultaneously. The fact that suppression of the VOR movement has been found

Fig. 20.7 The figure illustrates the spinocerebellar pathway from proprioceptors in the somatic muscles up to the cerebellum (blue lines). Efferent pathways descend to the vestibular nucleus and the reticular formation facilitating control of somatic activity (black lines). Drawing by IB Kjellevold Haugen

receptors, while the indirect pathways provide additional information essential for head and eye movements (Fig. 20.7). The spino-olivar pathway, which is synaptically interrupted by the inferior olive nucleus in the medulla oblongata, is one of the essential indirect pathways. The olive nucleus receives a substantial input from the retina and visual cortex through the superior colliculus and the pretectal nucleus. Some of this information is projected to the lobus flocculonodularis and contributes to the tuning of the vestibule-ocular reflex. The cerebellum also receives ocular proprioception through the trigeminal nuclei because receptors in the extraocular muscles convey their sensory information via the ophthalmic division of the trigeminal nerve. Fibers from the trigeminal nuclei will, in turn, terminate in the spinocerebellum.

This neural arrangement indicates that the proprioceptive information plays a vital role in tuning interactions between somatic and oculomotor control. Age-related changes altering the morphology of the receptors or associated afferent pathways would cause shifts in the supranuclear input and give rise to oculomotor anomalies.

The Muscle Spindle

The muscle spindle is regarded as one of the main sources of proprioception and plays a vital role in the motor control of most somatic muscles. Animal experiments have revealed that the sensitivity of the muscle spindles declines with age. The reason for the decline is not known, but it may be associated with age-related deficits in cholinergic signal transduction.22 Deficits in the transport, synthesis, and/or

Fig. 20.9 Drawing of a muscle spindle with interrupted intrafusal fibers and empty periaxial space. The dotted line illustrates the level from where the micrograph is taken (see Fig. 20-8). Drawing by IB Kjellevold Haugen

could be caused by degeneration of the spindle after their role had been fulfilled in the earlier stages of life could be sustained, but the presence of the same features in infant subjects jeopardizes this view.27 The alternative view is that they have become phylogenetically redundant. However, the presence of redundant muscle spindles does not preclude the possibility that there might be other receptors present that are capable of fulfilling a proprioceptive role.

Tendon Receptors

Although putative myotendinous receptors have been noted in the extraocular muscles of various species, the classical Golgi tendon organ (GTO) form has not been reported in man.27 Despite the absence of GTOs and functional muscle spindles, there seems to be a proprioceptive signal arising from the human EOMs. Intracranial ophthalmic neurectomy in monkeys has revealed ophthalmic nerve fibers entering EOMs.28 Most recent papers seem to support this finding and favor the ophthalmic nerve as the main route for proprioception also in man.29 Clinical observations of oculomotor deficits in patients with herpes zoster ophthalmicus add credence to this view.30 The interest in potential sources of proprioception was renewed following reports on alterations in position sense in patients who had undergone surgery in this region of the muscle.31 Recent studies have confirmed the presence of tendon receptors in human EOM, and their resemblance to the nerve endings at the musculotendinous junction in cats has led to the contention that they are of the same

Fig. 20.10 Micrograph showing a transverse section through a myotendinous cylinder at the distal end of a Felderstruktur fiber

Fig. 20.11 The figure illustrates the structural organization of the myotendinous cylinder. The dotted line illustrates the level from where the micrograph is taken (see Fig. 2010). Drawing by IB Kjellevold Haugen

origin.32 Morphological varieties of this receptor have resulted in a variety of names, such as myotendinous cylinders33,34 and musculo-tendinous complexes.35 In the literature, these terms are often used as synonyms.36

These receptors are innervated by unmyelinated and myelinated nerve fibers with diameters ranging from 1 to 6 m. These small, afferent nerve fibers are regularly occurring features throughout the length of the myotendinous junction in mature subjects, but infrequent in infants.27, 37,38 The distally located nerve terminals are exclusively associated with the multiply innervated Felderstruktur fibers (Fig. 20.10 and 20.11). Previous studies have demonstrated an age-related change in the number of these fibers, which suggests a corresponding decline in the number of receptors.39 The literature promotes the view that proprioception from extraocular

muscles contributes to the reflexes that serve to stabilize the visual image on the retina. The notion that reduction in proprioception can cause decline of both the vestibule-ocular reflex and the optokinetic reflex cannot be dismissed.

However, several sensory systems contribute to stabilizing the visual image on the retina during head movements, and proprioception from the muscles in the head and neck must also be taken into consideration. A recent study has raised the question of whether the cervico-ocular reflex, which serves to stabilize the retinal image through rotations of the neck, can compensate for the deficits in the vestibuleocular reflex (VOR). The results from this study are intriguing and suggest that there is a synergistic function between the VOR and cervico-ocular reflex, and that the latter reflex can be upgraded to compensate for the decline in VOR that occurs with age.40

Age-related Changes in the Cerebrocerebellum

and the Pontocerebellar Pathway

The pontine nuclei receive substantial input from the cerebral cortex, which is further projected to the cerebellum through the middle cerebral peduncles. The vast majority of the afferent fibers that terminate in the two hemispheres of the cerebellum originate from the pons, and the cerebrocerebellum is therefore also referred to as the pontocerebellum. The function of the pontocerebellum is primarily planning and control of somatic muscle activity and timing of their contractions, including that of the extraocular muscles. Single-cell recordings from selected cortical regions have revealed neuronal activity prior to conjugate eye movements.12 The most essential of these regions are the frontal eye field and the parietal eye field. These two cortical areas are responsible for saccadic and pursuit eye movements, respectively, and have neural pathways that descend to premotor structures in the pons and associated areas in the brainstem.

The Frontal Eye Field (FEF)

The FEF is located in the frontal lobe of each hemisphere and coincides with the cortical area 8 of Brodmann. The neural pathways from the FEFs descend through the capsula interna, and decussate before terminating in premotor regions such as the superior colliculus, pretectal nucleus, and paramedian pontine reticular formation (PPRF). From this, it follows that neural stimulation of the right FEF initiates conjugate eye movements to the left, while the left FEF initiates movements to the right—in both cases, the movements will be saccadic in nature. These jerky discontinuous eye movements have dynamic characteristics that vary to a certain degree according to the nature of the saccade. The basic features, however, can be summarized as rapid accelerating eye movements of short duration with a peak velocity of about 400–600 deg/s and an amplitude of less than 15 degrees.

Fig. 20.12 Micrograph of the reticular formation of a monkey. The reticular formation is an ill-defined collection of neurons and fibers that extends through several regions of the brainstem, including the medulla, pons, and mesencephalon

Several studies have documented age-related changes in duration, velocity, acceleration, and accuracy of horizontal saccades.40,41,42 This indicates that the subject’s ability to redirect the central retina to a new object of interest declines with age. In general, saccades disturb visual processing because the visual acuity is reduced while the visual image is swept across the retina. If the speed of the saccades is reduced, this disturbance is no longer kept to a minimum. A reduction in accuracy will disturb visual processing even further, because a corrective movement will extend the time allocated to refixate the target. Similar deficits have been found in the control of vertical saccades.43 In a recent study, it was found that age deteriorates the ability to trigger regular volitional vertical saccades, but not the ability to produce reflex initiated saccades.44 These findings were defended to reflect the fact that there is a widespread atrophy of both gray and white matter in the cerebral cortex, affecting both the frontal lobe and the posterior cortex. The neural pathway for volitional vertical saccades originates in the frontal eye field and projects to the rostral interstitial nucleus of the medial longitudinal fasciculus (rMLF). Reflexive saccades, on the other hand, can be generated by the occipitaltectal system and are hence not affected. In a more recent study by the same authors, it was found that aging only has a minimal affect on the overall accuracy of vertical saccades due to control mechanisms in the brainstem and cerebellum.45

The clinical implications of age-related changes in the frontal eye field are not limited to deficits in saccadic eye movements, but may also affect the vergence system. The neural pathway for the vergence system is not fully explored, but neurons in the primary visual cortex are believed to provide input to the frontal eye field. The FEF and possibly other visual areas provide input to cells with vergencelinked activity in the cerebellum. Cerebellar signals go to supraoculomotor areas,

which in turn go to motor neurons in the abducens nucleus or the medial rectus subnucleus—for divergence or convergence, respectively. Atrophy of cortical neurons could also affect the interaction between the motor neurons in the III nerve nuclear complex and jeopardize the simultaneous contraction of smooth muscles in the ciliary body/iris and the striated muscle fibers in the medial rectus.

The Parietal Eye Field (PEF)

Clinical observations of pursuit eye movements in patients of different age groups have shown that older patients have difficulties in following slowly moving targets.42 The control of the smooth pursuit movements arise from the lateral parietal and mid-temporal cortices—also referred to as the parieto-occipito-temporal junction in previous literature. The cluster of cortical neurons that constitute the left parietal eye field controls smooth pursuits to the left, and a similar ipsilateral innervation applies for the right eye field, which controls pursuits to the right. The immediate initial motor signal arises from neurons in the (PPRF), which in turn has neural pathways to the cerebellum and superior colliculus. Disorders of the pursuit system can hence be caused by changes in neurons or the associated neural pathways of the PEF, the PPRF, the cerebellum, or segments of the brainstem. The function of this system can be monitored by making the patient trace a moving target with their eyes. The patient’s inability to perform pursuit movements is usually compensated by a number of small saccades to maintain fixation. These types of saccadic eye movements are frequently observed in elderly patients with age-related changes in their pursuit motor system. However, disorders of the smooth pursuit system in elderly patients may not be exclusively associated with structural changes. They can also be caused by other factors associated with old age, such as medication and fatigue.

The Paramedian Pontine Reticular Formation (PPRF)

The reticular formation is responsible for coordination of complex patterns of body movements and facilitates simultaneous contraction of muscles involved in head and neck rotations, as well as eye movements. The ventral reticulospinal pathway is of special importance when it comes to movements of the extremities, while the pathway from the superior colliculus to reticulospinal neurons is of importance for movements initiated to move the head and upper body towards new objects of interest in the visual field. The median region of the reticular formation—the PPRF—is allocated to the control of horizontal conjugate eye movements, and is frequently referred to as the horizontal gaze center. It extends from the level of the trochlear nerve nuclei and up to abducens nuclei, and consists of neurons of variable sizes.12 This seemingly random distribution of neurons and nerve fibers gives the PPRF the reticular appearance from which the name is derived (Fig. 20.14). Other structures—also known to be associated with eye movement control—have extensive efferent projections to the PPRF. These